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51
Tonic Influence of the Sympathetic Nervous System
on Myocardial Reactive Hyperemia and on
Coronary Blood Flow Distribution in Dogs
PETER J. SCHWARTZ AND H. LOWELL STONE
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SUMMARY In two groups of dogs we studied the effect of right and/or left stellectomy on myocardial reactive
hyperemia (RH) and on coronary blood flow distribution. In the first group of 14 conscious dogs, the percent repayment of flow debt produced by a 10-second occlusion of the left circumflex coronary artery was recorded
with a Doppler ultrasonic flow probe and a hydraulic vascular occluder. The dogs were studied under control
conditions, after right stellectomy and after left stellectomy and after administration of propranolol and phentolamine. Right stellectomy did not affect RH. RH was significantly increased by left stellectomy from 476 ± 71%
to 622 ± 86% (+31%) at the spontaneous heart rate and from 407 ± 51% to 577 ± 106% (+42%) during pacing.
Propranolol significantly reduced RH from 447 ± 25% to 390 ± 27% (-13%) at the spontaneous heart rate and
from 456 ± 25% to 311 ± 24% (-32%) during pacing. Phentolamine significantly increased RH from 419 ± 63% to
517 ± 71% (+23%). Propranolol was effective after bilateral stellectomy, whereas phentolamine was not effective after left stellectomy. In the second group of 14 anesthetized dogs with constant heart rate (15 (im) microspheres were injected twice into the left atrium. The first injection provided a control measurement; in nine dogs
the second injection was made after left stellectomy. Left stellectomy significntly increased the left ventricular
endocardial to epicardial ratio from 1.7 ± 0.03 to 1.23 ± 0.04. We conclude that the sympathetic nervous system
has a tonic influence on coronary circulation and that left stellectomy increases the ability of the coronary bed to
dilate and improves the endocardial perfusion.
UNILATERAL stellate ganglion blockade or ablation recently was found to produce marked changes in ventricular
vulnerability to fibrillation1-2 and also to affect excitability
of the ventricles.3 These studies suggested a tonic influence
of the sympathetic nerves on cardiac function and avoided
the shortcomings inherent in the use of nerve stimulation
and autonomic drugs. The effect of tonic sympathetic
nervous system activity on coronary flow and the distribution of flow across the ventricular wall remains an important unanswered question as stated by Berne.4 This study
was designed to investigate the tonic effect of sympathetic
activity on the coronary reactive hyperemic response to
short-lasting occlusions and the distribution of coronary
flow across the myocardial wall.
Myocardial reactive hyperemia (RH) is thought to depend on either hypoxia-induced release of vasoactive metabolites5 or myogenic relaxation of coronary vascular
smooth muscle in response to loss of the stretch stimulus
provided by arterial blood pressure.6'7 A possible role of
cardiac sympathetic nerves in RH has been generally discounted,5' 8~10 but the evidence in favor of this concept
does not seem conclusive. Transmural distribution of coronary blood flow is affected by systolic extravascular presFrom the Department of Physiology and Biophysics and Marine
Biomedical Institute, University of Texas Medical Branch, Galveston,
Texas, and the Istituto Ricerche Cardiovascolari, Universita di Milano and
Centro Ricerche Cardiovascolari, C.N.R., Milano, Italy.
Supported in part by Grants HL-18798 and HL-14828 from the U.S.
Public Health Service.
Dr. Schwartz was a visiting associate professor on leave from the
University of Milan.
Address for reprints: Peter J. Schwartz, M.D., Istituto Ricerche Cardiovascolari, Universita di Milano, Via F. Sforza 35, 20122 Milano, Italy.
Original manuscript received January 19, 1976; accepted for publication
November 18, 1976.
sure and by the resistance of the large tributary arteries."
A lower tissue Po2 is present in the subendocardial layers
of the left ventricle," which are known to be more vulnerable to ischemia than subepicardial layers.12 However,
studies on the distribution of microspheres show that the
endocardium has a higher blood flow than the epicardium
[endocardial to epicardial ratio greater than 1] in animals
with normal coronary arteries, as reported by most authors."1 13 Because redistribution of blood flow from the
epicardium to the endocardium results from dilation of
large intramural supply arteries," the sympathetic nerves
may be implicated. Increases in sympathetic activity, as
produced by stimulation of the left stellate ganglion
(LSG)14 or duplicated by isoproterenol,15 decrease endo/
epi ratio. In contrast, propranolol increases the endo/epi
ratio,16'17 the effect being attributed primarily to the
reduction in heart rate.'"
Methods
Thirty-three mongrel dogs ranging in weight from 17 to
23 kg were used in this study. Of these, 19 were prepared
for chronic studies and 14 were used in acute studies.
CHRONIC STUDIES
The dogs used for this portion of the study were free of
heartworms and in good health prior to surgery. They
were anesthetized with sodium pentothal (30 mg/kg, iv)
and intubated. The level of anesthesia was maintained
with a mixture of oxygen, nitrous oxide, and halothane.
The left side of the thorax was entered through the 3rd
intercostal space and subsequently the 5th intercostal
space. The LSG, the ansa subclavia, and the rami communicantes from T, to T4 were identified. A length of nylon
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CIRCULATION RESEARCH
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monofilament suture was placed around the caudal portion of the ganglion near the entry of the T3 ramus and a
second piece of suture was placed around the ansa subclavia at the cranial part of the ganglion. Both monofilament
sutures were buried subcutaneously near the vertebrae on
the left side. Care was exercised to make certain that the
sutures remained loose around the ganglion to prevent
undue tension on it.
The heart was exposed through the 5th intercostal
space. The left circumflex coronary artery was dissected
free of surrounding tissue from its origin for approximately
2.5-3 cm. Usually sufficient lengths of artery were obtained for the implantation of the flow probe and hydraulic
occluder without sacrificing large epicardial branches.
Great care was exercised in the dissection of this vessel to
maintain the adventitia intact; and, in so doing, adipose
tissue surrounding the vessel was not removed.18 A Doppler ultrasonic flow probe was placed around the vessel
and secured in place. A hydraulic vascular occluder was
placed around the vessel distal to the flow probe. A solid
state pressure transducer (Konigsberg, model P-20) was
positioned in the left ventricular cavity through an incision
in the left ventricular apical dimple. A polyvinyl catheter
was passed through the left atrial appendage to the left
atrium and secured in place. Stainless steel electrodes
were sutured to the right atrium about 2 cm apart. All lead
wires and the left atrial catheter were brought out of the
chest and tunneled to the dorsal surface of the neck where
they exited from the skin. The chest incision was closed
and the dog was allowed to recover.
Studies were started 3-4 weeks after implantation. Recordings of the left circumflex coronary artery flow velocity,19 left ventricular pressure, left atrial pressure, and the
electrocardiogram (lead 2) were made on an eight-channel
Beckman direct-writing oscillograph. The derivative of left
ventricular pressure (dP/dt) was obtained by an analog
differentiator with a time constant of 0.01 second and a
linear frequency response to 65 Hz. This signal was recorded on the direct-writing oscillograph. The electrocardiogram was used to trigger a cardiotachometer for measurement of heart rate. The signals also were recorded on
magnetic tape (Ampex FR-1300) for later analysis. The
stainless steel electrodes were connected to a Grass S4
stimulator through an isolation unit. Pulse duration was
set at 5 msec with voltage high enough to be able to sustain
a paced heart rate. Four 10-second occlusions of the left
circumflex were made at 10-min intervals. Two occlusions were repeated with the heart paced at 150 beats/min.
Thus, at least six trials were made during each experiment.
For most of the dogs three experiments were performed
under each of the conditions under study, with the experiments separated by at least 2-3 days. In one of these
experiments, both under control conditions and after bilateral stellectomy, the six trials were repeated after administration of propranolol (1 mg/kg) or phentolamine (1
mg/kg). a-Adrenergic blockade was tested by the intravenous injection of phenylephrine. Flow debt, reactive hyperemic flow, and repayment of flow debt were calculated
as described by Coffman and Gregg:20
Flow debt = control flow rate x duration of occlusion.
Reactive hyperemic flow = (integral of the flow curve
VOL. 41, No. 1, JULY 1977
during reactive hyperemia) - (control flow rate x duration of reactive hyperemia).
Percent repayment of flow debt = (reactive hyperemic
flow/flow debt) x 100. [For simplicity, the percent repayment will be referred to in text and tables as reactive
hyperemia (RH).]
When the control study had been completed, the dogs
were anesthetized a second time in the same manner. The
right chest was entered through the 3rd intercostal space.
The right stellate ganglion (RSG) was dissected free, isolated in the same manner as the LSG, and then completely
excised.
Two weeks after the removal of RSG, the experiments
were repeated as under control conditions. At the end of
the last experiment, the dogs were anesthetized with sodium pentothal (30 mg/kg,. iv) and the nylon monofilament suture around the LSG was exposed. Both sutures
were pulled simultaneously, culminating in the destruction
of the LSG. After 6 days, a sequence of three experiments
was repeated, including one with propranolol (12 trials).
At this point, both stellate ganglia had been removed; this
resulted in an almost complete (from a functional point of
view) cardiac sympathetic denervation.
In three dogs the study began after right stellectomy
(RSGx), and in one, after left stellectomy (LSGx). Two
dogs were studied under control conditions and after
RSGx. For technical reasons, it was not possible to continue the study with LSGx. In two dogs LSGx was performed without prior RSGx.
When the dogs were killed the left circumflex coronary
artery was injected with acrylic and allowed to harden.
The cross-sectional area was calculated from the dimension of this acrylic cast. Velocity of flow was converted to
volume flow by multiplying the velocity by the crosssectional area.
To reduce experimental variability, the data were
grouped in the following way: the first trials of the control
sessions were averaged and compared with the average of
the first trials of the experimental sessions (after RSGx or
LSGx) and so on with the second, third, and fourth trial of
every session. Data were analyzed by Student's /-test for
paired observations. All values are expressed as means ±
SE.
ACUTE STUDIES
Fourteen mongrel dogs were used for this portion of the
study. The dogs were anesthetized with a-chloralose (80
mg/kg, iv), intubated, and ventilated with a Harvard respirator. The heart was exposed on the right side and the
sinoatrial node crushed. Pacing electrodes were sutured to
the right atrium and pacing of the heart was begun at 162
beats/min. The right chest was closed and the dog was
turned for exposure of the heart from the left side. The
heart was exposed and catheters were placed in the left
atrium and coronary sinus. An electromagnetic flow probe
was carefully placed around the left circumflex artery.
Ligatures were placed around the LSG. Both femoral
arteries were cannulated. A catheter-tip pressure transducer (Millar) was passed into the left ventricle and a
woven dacron catheter was positioned in the thoracic aorta
to measure pressure.
STELLECTOMY AND CORONARY CIRCULATION/Sc/wonz and Stone
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After dissection of the coronary artery, both cervical
vagi were cut to increase sympathetic activity. The dogs
were allowed to stabilize for 1 hour while blood gases were
determined with an Instrumentation Laboratories model
213 blood gas analyzer. The arterial pressure catheter was
connected to a Statham P23 Db pressure transducer zeroed
to the midsternal line. The electromagnetic flow probe was
connected to a Zepeda flowmeter. All signals were recorded on an eight-channel Beckman recorder. Continuous recordings of the electrocardiogram, left ventricular
pressure, the first derivative of left ventricular pressure,
arterial pressure, heart rate, and left circumflex coronary
artery flow were made as described previously. The zero
flow signal was determined before and after each injection
of microspheres. Blood samples were taken from the arterial catheter and the coronary sinus catheter prior to each
microsphere injection. The dog's body temperature was
maintained at 37 ± 0.5°C during the course of the experiment. The flow probe was calibrated with the dog's blood
at the termination of the experiments.
After the stabilization period the distribution of coronary flow across the myocardium was determined by the
injection of carbonized microspheres into the left atrium.
The microspheres (3M Co.) were 15 ± 5 /xm in size,
labeled with either 14lCe or 85Sr. The size distribution of
the microsphere was determined by microscopic examination. The microspheres were drawn up into a syringe and
mixed well before injection, as described previously.21 A
total of approximately 8.5 x 105 microspheres was injected. The microspheres were flushed into the atrium
with saline. A second injection of microspheres was made
45 minutes after the first after ablation of the LSG in nine
dogs while five dogs served as controls. Again, blood
samples were taken from both the artery and coronary
sinus. After the second injection of microspheres, the dogs
were killed and the hearts removed and washed free of
blood. The hearts were divided into left ventricular free
wall, septum, and right ventricular free wall. The left
ventricular free wall was further divided from base to apex
into samples of 1-3 g. Each small sample was cut into
equal epicardial and endocardial portions and placed in
counting vials. The samples were weighed and counted in
a 7.6 cm Nal well-type scintillation detector (Searle Analytic). The samples were counted for 10 minutes to establish a proper counting efficiency. The radioactivity from
each sample was expressed as activity per gram of sample
and the counts in each sample were corrected for nuclide
interaction. The endocardial to epicardial ratio for each
sample was determined. The samples comprising the central portion of the left ventricular free wall were used in
the analysis of the data in each dog. The average value for
the control and experimental periods was obtained by
using the same location on the free wall and number of
samples from each subject.
Myocardial oxygen consumption was calculated from
the left circumflex coronary artery flow and the arteriovenous oxygen content difference. Statistical analysis was
performed using a paired r-test.
Results
EXPERIMENTS IN CONSCIOUS DOGS
Of the 19 dogs instrumented and completely studied in
the control condition, one died of postsurgical complications after the right stellectomy, and technical failures in
two dogs made the continuation of the study impossible.
In two other dogs that were eventually killed because of an
acute infection, RH decreased by 27% after bilateral
stellectomy. The results reported here are based, therefore, on 14 dogs in which the various devices implanted
performed well for the necessary periods of time, ranging
from 50 to 65 days following surgery. In one of these dogs
the LSG was damaged and, therefore, ablated in the first
surgical session. The percentage of dogs that could not
participate in the entire study is comparable with those
reported in previous investigations.10
Effect of RSGx
In five dogs (24 experiments and 88 trials), RSGx did
not affect RH (Tables 1 and 2; Fig. 1). The decrease from
486 ± 45% to 460 ± 40% (-5%) was not statistically
significant. RSGx had a minor effect on blood pressure
(—4%) but significantly decreased heart rate (-17%) and
mean coronary flow (-17%). By contrast, dP/dt increased significantly (+13%).
Since heart rate, which is a major determinant of mean
coronary flow, was reduced by RSGx, the study was repeated keeping the heart rate constant by atrial pacing.
RH was unaffected by RSGx plus pacing. The increase
from 453 ± 47% to 456 ± 56% ( + 1%) was insignificant.
Pacing suppressed the decrease in mean coronary flow
produced by RSGx (from 46 ± 17 to 47 ± 16 ml/min at
TABLE 1 Effect of Unilateral Stellectomy, and a- and ^-Blockade on Reactive Hyperemia
No.
of
,
dogs
RSGx
RSGx + P
LSGx
LSGx + P
/3-Blockade
/J-Blockade + P
a-Blockade
a-Blockade + P
„
Reactive hyperemia (%)
r
ments
24
25
16
9
4
4
14
10
Tna
Control
88
48
60
21
28
16
42
30
53
486 d- 45
453 it 47
476 it 71
407 ii 51
447 it 25
456 dt 25
419 i: 63
368 ± 21
Change
Significance
Experimental
460
456
622
577
390
±
±
±
±
±
40
56
86
106
27
311 ± 24
517 ± 71
423 ± 34
-5
+1
+ 31
+ 42
-13
-32
+ 23
+ 15
NS
NS
P < 0.005
P < 0.05
P <0.01
P < 0.001
P < 0.01
P < 0.01
RSGx = right stellectomy; LSGx = left stellectomy; P = pacing; NS = not significant. All values are
means ± SE.
CIRCULATION RESEARCH
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VOL. 41, No. 1, JULY 1977
TABLE 2 Effect of Unilateral Stellectomy on Reactive Hyperemia and Other Hemodynamic Variables
Left stellectomy
Control
RH
HR
BP
MCF "
476
89
140
3132
36
±
±
±
±
±
71%
9
9
180
7
LSGx
622 ±
80 ±
130 ±
3172 ±
32 ±
86%
9
7
290
4
Change
+ 31
-10
-7
+1
-11
Right stellectomy
Significance
Control
P < 0.005
P < 0.05
NS
NS
NS
486 + 45%
106 + 7
137 ± 5
2994 + 345
41+9
RSGx
460
88
131
3396
34
± 40%
± 3
± 5
± 287
± 7
Change
-5
-17
-4
+ 13
-17
Significance
NS
P < 0.05
NS
P < 0.05
P < 0.05
LSGx = left stellectomy; RSGx = right stellectomy; RH = reactive hyperemia; HR = heart rate (beats/min); BP = blood pressure (mm
Hg); dP/dt^a, = first derivative of left ventricular pressure (mm Hg/sec); MCF = mean coronary flow (ml/min); NS = not significant. All
values are mean ± SE.
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150 beats/min), suggesting that it was merely dependent
on the change in heart rate.
In one of these five dogs the RSG was ablated after
LSGx; this resulted, therefore, in a bilateral stellectomy.
RSGx only slightly reduced RH also in this dog; this
indicated that the lack of effect on RH of RSGx was
independent of the sequence of experimental conditions.
Effect of LSGx
In five dogs (16 experiments and 60 trials) LSGx significantly increased RH, in comparison to the values after
RSGx (three dogs) and to control values (two dogs), from
476 ± 71 % to 622 ± 86% (+31 %) (Tables 1 and 2; Fig.
1). There were minor changes in blood pressure, dP/dt,
and mean coronary flow. The decrease in heart rate was
small but significant and the study was repeated in three
dogs while heart rate was kept constant by arterial pacing:
RH was found to be increased more, from 407 ± 51 % to
577 ± 106% ( + 42%).
The dog in which ablation of the LSG in the first
surgical session did not permit the recording of control
values was the one constantly showing the largest RH (811
± 52%).
The peak hyperemic flow was 123 ± 11 ml/min before
removal of the LSG and fell to 106 ± 4 ml/min (-14%).
The decrease in the peak flow response to a 10-second
occlusion was not significant.
Effect of 13-Blockade
In four dogs (four experiments and 28 trials), propranolol (1 mg/kg) significantly reduced RH from 447 ± 2 5 %
to 390 ± 27% (-13%) (Tables 1 and 3; Fig. 1). Propranolol significantly decreased dP/dt and mean coronary flow.
The decreases in heart rate and blood pressure were not
significant but it must be noted that the reduction in heart
rate (-16%) is smaller than that expected, probably because in two of the dogs in which propranolol was tested
the RSG had been ablated. As with RSGx, the reduction
in mean coronary flow was no longer present when heart
rate was kept constant by atrial pacing. Pacing, however,
did not abolish the effect of propranolol on RH, which was
actually potentiated: RH was decreased from 456 ± 2 5 %
to 311 ± 24% (-32%).
The opposite effect produced by LSGx and propranolol
prompted us to investigate whether the drug still could
influence RH in a heart largely deprived of sympathetic
innervation as in bilaterally stellectomized dogs. In two
dogs after bilateral stellectomy, propranolol significantly
decreased (-29%) RH when the heart rate was kept
constant by pacing. Also, with spontaneous heart rate,
propranolol reduced RH, but to a lesser degree (-10%).
Effect of a-Blockade
In seven dogs (14 experiments and 42 trials) phentolamine (1 mg/kg) significantly increased RH in comparison
to control values, from 419 ± 6 3 % to 517 ± 7 1 %
(+23%) (Tables 1 and 4; Fig. 1). There were no significant
700
650
LSG x
600
p LSGx + P
550
c
a
E
>»
a
a
a.
«
500
4 50
400
350
S
A BBlock + P
300
control
experimental
FIGURE 1 This figure summarizes the results obtained in all the
dogs and shows clearly the similar effects produced by left stellectomy (LSGx) and phentolamine (a-block) on reactive hyperemia
(RH), and the opposite effects produced by propranolol (fi-block)
independent of pacing (P). It shows also the lack of effect of right
stellectomy (RSGx). The points represent the means of all the trials;
for clarity, the standard errors are not included but may be found in
Table 1.
STELLECTOMY AND CORONARY CIRCULATION/Sc/wartz and Stone
55
TABLE 3 Effect of Propranolol on Reactive Hyperemia and Other Hemodynamic Variables
Spontaneous HR
Control
RH
HR
BP
MCF "
447
91
134
3508
37
±
±
±
±
±
25%
5
5
113
13
Propranolol
390
76
126
3010
30
±
±
±
±
±
Pacing
Change
27%
7
6
133
12
Significance
-13
-16
-6
-14
-19
P < 0.01
NS
NS
P < 0.005
P < 0.05
Control
456 ±25%
153
130 ± 2
3098 ± 239
44 ± 16
Propranolol
311
153
118
2501
45
Change
Significance
± 24%
-32
P < 0.001
±2
± 222
± 17
-9
-19
±2
NS
P < 0.001
NS
Change
Significance
± 34%
+ 15
±3
± 240
±2
+2
+ 16
+3
P < 0.01
NS
NS
P < 0.05
NS
Abbreviations as in Table 2. All values are mean ± SE.
TABLE 4 Effect of Phentolamine on Reactive Hyperemia and Other Hemodynamic Variables
Pacing
Spontaneous HR
Control
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RH
HR
BP
MCF ""
419
91
134
3171
28
±
±
±
±
+
63%
7
2
262
3
Phentolamine
517
113
116
3474
30
+ 71%
± 12
± 17
± 272
±2
Change
(%)
Significance
+ 23
+ 24
-13
+ 10
+7
P < 0.01
NS
NS
NS
NS
Control
368
150
134
2906
37
± 21%
±2
± 277
±2
Phentolamine
423
150
137
3363
38
Abbreviations as in Table 2. All values are mean ± SE.
changes in heart rate, blood pressure, dP/dtmax, or mean
coronary flow after phentolamine blockade during spontaneous rhythm. With pacing, a small but significant increase in dP/dtmax was found (2,906 mm Hg/sec to 3,363
mm Hg/sec) after blockade. With heart rate kept constant
by pacing in five dogs (10 experiments and 30 trials),
phentolamine still significantly increased RH from 368 ±
21% to 423 ± 34% (+15%). Apparently a-blockade was
duplicating the effects of LSGx; this suggested interference with the effects of neural activity passing through the
LSG. In two dogs phentolamine was used after LSGx. In
them, a-blockade did not modify RH during spontaneous
heart rate. However with pacing, there was a slight, but
not significant, decrease in RH.
ACUTE EXPERIMENTS
In nine dogs the transmural coronary blood flow distribution was determined by measuring the left ventricular
subendocardium-subepicardium ratio of distribution of radioactive microspheres before and after left stellectomy
(Table 5). LSGx significantly increased the endo/epi ratio
from 1.17 ± 0.03 to 1.23 ± 0.04; this finding indicates a
better perfusion of the subendocardium. Heart rate was
kept constant by atrial pacing; and blood pressure, dP/dt,
TABLE
mean coronary flow, and O2 consumption were almost
unchanged.
In the five control dogs in which no experimental procedures were conducted between the first and second injection of microspheres, the endo/epi ratio remained practically unmodified and showed only a slight decrease, from
1.12 ± 0.24 to 1.11 ± 0.24.
Discussion
MYOCARDIAL REACTIVE HYPEREMIA
To evaluate the possible role of the sympathetic nervous
system in the phenomenon of RH, the following steps
were considered important: (1) to measure RH before and
after surgical denervation, the number of dogs being of
secondary importance with respect to the number of trials
and sessions in each condition, in order to minimize individual variability from day to day; (2) to compare surgical
denervation with pharmacological blockade in order to
gain insights into the mechanisms involved and to verify if
the latter can duplicate the former, as often is assumed;
(3) to perform the entire study under conditions of spontaneous and paced heart rate since both surgical and pharmacological interventions on the sympathetic innervation
5 Effect of Left Stellectomy on Transmural Coronary Blood Flow Distribution
Endo/epi
HR (beats/min)
BP (mm Hg)
dP/dt^, (mm Hg/sec)
MCF (ml/min)
O2 consumption (ml/min)
Control
LSGx
Significance
1.17 ± 0.03
1.23 ± 0.04
P < 0.025
162
124
2130
30
3.28
162
±
±
±
±
6
135
2
0.37
124
1951
29
3.16
±
±
±
±
7
185
3
0.39
NS
NS
NS
NS
NS
Endo/epi = endocardial to epicardial ratio; other abbreviations as in Table 2. All values are mean ±
56
CIRCULATION RESEARCH
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alter, by reducing heart rate, hemodynamic parameters
of possible importance such as mean coronary flow; (4) to
study conscious dogs and thus avoid the shortcomings
associated with anesthesia.
Vasodilation in response to a metabolite produced by
even mild degrees of anoxia5 and the myogenic properties
of vascular smooth muscle6-7 are presently the factors
most often implicated in the production of RH.22 The
involvement of any neural mechanism has been practically
discarded on the basis of several experimental data, none
of which seems conclusive. Olsson and Gregg23 found that
atropine and guanethidine increased RH. This effect was
considered to be dependent only on heart rate increases,
but the experiments were not repeated during cardiac
pacing. Gregg et al.10 studied five dogs with cardiac neural
ablation and the degree of reactive hyperemic response
(300-700%) was considered comparable to that found in
normal dogs (500 ± 200%).24 These experiments suffer,
however, from the lack of internal controls and, with such
large variation in individual control values, changes produced by denervation in each dog could not be excluded.
Eikens and Wilcken" found that propranolol reduced the
percent repayment from 471 ± 21% to 325 ± 28% (a
reduction of 31%), a change strikingly similar to that
obtained in our experiments with pacing (Table 3). These
authors attributed this reduction to the lower preocclusion
mean coronary flow.
Right stellectomy, the LSG being either intact or sectioned, did not affect RH. Decreases in mean coronary
flow and in heart rate were prevented in the experiments
with pacing while RH remained unaffected by RSGx.
The increase in dP/dt observed after RSGx confirms the
suggestion3 that after unilateral stellectomy a baroreceptive reflex increases the sympathetic activity running
through the contralateral stellate ganglion. Due to the
predominant innervation of the left ventricle by fibers
passing through the LSGx, this would result, as observed,
in an actual increase in contractility.
In contrast, LSGx significantly increased RH. Hemodynamic changes that might explain this finding were not
present and the decrease in mean coronary flow was similar to that associated with RSGx and unmodified RH, and
with propranolol and reduced RH. Thus, a lower level of
mean coronary flow, perse, does not influence RH. This is
at variance with the suggestion offered by Eikens and
Wilcken9 to explain the reduction in RH produced by
propranolol.
RSGx performed after LSGx resulted in a minor decrease in RH. The dog in which LSGx was performed
initially was the one showing the largest RH. The difference between the effect of RSGx and LSGx is therefore
extremely likely to be independent of the sequence of
ablation. A possible explanation for the difference observed is that the circumflex coronary artery is predominantly innervated by the LSG.18-25
The cardiac sympathetic nerves mediate both a- and /}adrenergic effects4 and their section, of course, interferes
equally with both of them. The increase in RH produced
by LSGx, which represents "the ability of coronary bed to
dilate,"24 suggested that a vasoconstrictor activity (possibly of the a type) was dominant. This suggestion was
VOL. 41, No. I.JULY
1977
confirmed by finding that a-blockade increased RH as did
LSGx, although to a lesser degree. The difference in
magnitude is probably due to the fact that whereas LSGx
completely interrupts all the fibers passing through the
ganglion, a-blockade may often be less than 100% effective. An additional important finding was that a-blockade
after LSGx was no longer effective.
Propranolol decreased RH. When heart rate was kept
constant by pacing, preventing the reduction in mean
coronary flow, the effect was even more marked. /3-Blockade leaves unopposed the a-vasoconstrictor effect and it is
not surprising that this results in a decreased RH. The
opposite effect of LSGx and propranolol are, therefore,
understandable. Unfortunately, too often /3-blockade is
still assumed to duplicate cardiac sympathetic denervation. Moreover, as suggested by the decrease in RH observed after bilateral stellectomy, propranolol is likely to
affect the capability of coronary vessels to dilate by antagonizing the /3-agonist effects of circulating epinephrine
released from the adrenals. Hence, epinephrine would act
only on the a-receptors of the coronary vessels.
Coronary artery occlusion, through excitation of cardiac
sympathetic afferent fibers,26'27 elicits a reflex increase in
cardiac sympathetic efferent activity.28 This cardiocardiac
sympathetic reflex, which is partially responsible for the
arrhythmias associated with coronary artery occlusion,29
may contribute to the sympathetic effect on RH by increasing the vasoconstrictor tone.
Szentivanyi and Juhasz-Nagy30 reported that section of
the coronary sympathetic vasomotor fibers, in acute experiments, diminishes or abolishes RH. According to
Berne,5 however, this finding is suggestive of unresponsive
vessels in deteriorating preparations. Our data in two
acutely infected dogs support Berne's opinion, since a
decrease in RH following bilateral stellectomy was observed.
The emerging concept of the cardiac sympathetic nerves
representing a limiting factor for reactive hyperemia and
the capability of the coronary bed to dilate, should not
lead to the unjustified conclusion that coronary vasoconstriction of clinical importance may result from increased
sympathetic activity.
MYOCARDIAL BLOOD FLOW DISTRIBUTION
Microspheres injected into the left atrium distribute
systematically and, because of their size, are trapped in
precapillary vessels in their first transit through the circulation.31 The 15-/xm microspheres give a good estimate of
flow distribution17 and have been used to study regional
myocardial blood flow.32-33 It was found in our series of
dogs that LSGx significantly increased the endo/epi ratio
of distribution of microspheres. This effect was not associated with, and therefore was independent of, changes in
blood pressure, dP/dt, mean coronary flow, and O2 consumption. These changes were probably minimized by the
fact that we kept heart rate constant by atrial pacing.
Thus, the interruption of the tonic activity present in the
cardiac sympathetic nerves remains as the major factor
responsible for the observed increase in the endo/epi ratio.
Theoretically, this may be due to either an increase in
endocardial perfusion or to a decrease in epicardial perfu-
STELLECTOMY AND CORONARY CIRCULATION/Sc/iwar/z and Stone
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sion or to a combination of both. The latter possibility
seems to be more likely since total flow from the circumflex artery did not change. It may be deduced that the
resistance to flow through subendocardial vessels has decreased, thus —with inflow constant —there would be a
greater portion of flow to the endocardium.
Uchida and Ueda14 used electrical stimulation of the
LSG and reduced the endo/epi ratio of myocardial blood
flow distribution. In their experiments, however, the
hemodynamic parameters were not controlled and the
results may have been partially dependent on, for instance, an increase in left ventricular pressure or contractility.
Propranolol has been found to increase the endo/epi
ratio; but this effect was associated with reductions in
heart rate.16-17 Since the endocardial flow occurs mainly in
diastole, a decrease in heart rate may be expected to
increase flow. In fact, Gross and Winbury16 found that
when heart rate is kept constant, propranolol does not
modify the endo/epi ratio. However, they also found that
a decrease in heart rate, per se, does not change the endo/
epi ratio unless there is an associated increase in coronary
resistance, which is thought to be a result of metabolic
autoregulation. Therefore, a pure /3-blocking action does
not seem to increase the endo/epi ratio of coronary blood
flow distribution.
Stellectomy interrupts both a- and /3-adrenergic activity. Since the net effect was an increase in the endo/epi
ratio without hemodynamic changes, one may speculate
that interruption of a dominant a-activity was the causative factor for the observed changes. A possible site of
action could be the intramural supply arteries. Interruption of a dominant a-constrictor activity would dilate
them, resulting in a redistribution of blood from the epicardium to the endocardium."
The significant change in endo/epi ratio was not large —
probably because of some limiting factors of our experimental conditions: (1) The heart was paced at 162 beats/
min to reduce the hemodynamic changes associated with
stellectomy, but at the same time the short diastolic interval also reduced the possibility of greatly increasing endocardial flow. (2) The changes in endo/epi ratio were not
obtained by electrical stimulation but were dependent on
the level of spontaneous activity present in the cardiac
sympathetic nerves. (3) Only part of the cardiac sympathetic innervation was ablated since a unilateral left stellectomy was performed. It is therefore likely that our
results have actually underestimated the tonic influence of
sympathetic nerves in limiting endocardial flow.
Conclusion
These two groups of experiments demonstrate that the
sympathetic nervous system has a tonic influence on coronary circulation. The cardiac sympathetic nerves exert a
continuous restraint on the capability of the coronary bed
to dilate and on the endocardial perfusion. This effect is
likely to depend on a coronary vasoconstrictor activity of
the a-receptor type.34-35 Recently we found that LSG
blockade markedly reduces the number of ectopic beats
associated with short-lasting coronary artery occlusion in
dogs.2 The favorable effect produced by LSGx on RH and
57
on endocardial blood flow distribution may contribute,
together with the decrease in ventricular vulnerability1 and
excitability3 produced by LSGx, in explaining this result.
Recent experiments by Feigl36 indicate that '"blood flow to
the heart, like that to other vascular beds, is potentially
under autonomic as well as metabolic control." This statement was based on data obtained with electrical stimulation. Our experiments, in which we observed the effects of
simply removing part of the cardiac sympathetic innervation, confirm and extend FeigPs concept and indicate that
the coronary circulation is actually under autonomic as
well as metabolic control.
Acknowledgments
We are grateful to G .E. Todd for expert technical assistance. We wish to
thank Dr. Keith Morgan of the Division of Nuclear Medicine for his
assistance with the microsphere study.
References
1. Schwartz PJ, Snebold NG, Brown AM: Effects of unilateral cardiac
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2. Schwartz PJ, Stone HL, Brown AM: Effects of unilateral stellate
ganglion blockade on the arrhythmias associated with coronary occlusion. Am Heart J 92: 589-599, 1976
3. Schwartz PJ, Verrier RL, Lown B: Effect of stellectomy and
vagotomy on ventricular refractoriness in dogs. Circ Res 40: 536540, 1977
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251-281
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9. Eikens E, Wilcken DEL: Myocardial reactive hyperemia and coronary
vascular reactivity in the dog. Circ Res 33: 267-274, 1973
10. Gregg DE, Khouri EM, Donald DE, Lowensohn HS, Pasyk S: Coronary circulation in the conscious dog with cardiac neural ablation. Circ
Res 31: 129-144, 1972
11. Winbury MM: Redistribution of left ventricular blood flow produced
by nitroglycerin. Circ Res 28 (suppl I): 140-147, 1971
12. Moir TW: Subendocardial distribution of coronary blood flow and the
effect of antianginal drugs. Circ Res 30: 621-627, 1972
13. Neill WA, Oxendine J, Phelps N, Anderson RP: Subendocardial
ischemia provoked by tachycardia in conscious dogs with coronary
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17. Becker LC, Fortuin NJ, Pitt B: Effect of ischemia and antianginal
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18. Denn MJ, Stone HL: Autonomic innervation of dog coronary arteries.
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19. Stone HL, Stegall HF, Kardon MB, Payne RM: Changes in aortic,
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20. Coffman JD, Gregg DE: Reactive hyperemia characteristics of the
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CIRCULATION RESEARCH
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The Canine Heart As an Electrocardiographs
Generator
Dependence on Cardiac Cell Orientation
L. VINCENT CORBIN, II, AND ALLEN M.
SCHER
SUMMARY Traditionally it is assumed that during cardiac depolarization the macroscopic current generators that
produce electrocardiographic voltages can be represented as a uniform double-layer source, coincident with the
macroscopic boundary between resting and depolarized cardiac fibers as measured with extracellular electrodes
("uniform" hypothesis). A segment of this boundary is thus considered as a current dipole oriented perpendicular to
the boundary. We present evidence that, contrary to the above, the effective dipoles largely parallel the long
axes of cardiac fibers ("axial" hypothesis). Calculated potentials in volume conductors differ markedly in the two
cases. The magnitudes of rapid local "intrinsic" deflections also differ markedly. In our experiments, potential fields
produced by stimulation at several cardiac sites and measured magnitudes of intrinsic deflections during normal
depolarization and that caused by stimulation support the axial hypothesis and are incompatible with the uniform
hypothesis. Our results suggest that axial orientation of sources is sufficiently strong so that predictions assuming the
uniform hypothesis would be seriously in error, although the axial theory alone does not exactly describe all the
measured potentials. Axial orientation of current generators must be considered in quantitative prediction of
electrocardiographic potentials. Further study of the geometry of the intracellular depolarization boundary and its
relation to fiber direction and to the frequency of lateral intercellular junctions is required to describe the generators
exactly.
THE ELECTROCARDIOGRAM (ECG) is of great utility in physiology and in cardiac diagnosis, but its shape has
not been quantitatively predictable from a knowledge of
intracardiac events. Such prediction, known as the electrocardiographic "forward" problem (usually dealing with
ventricular depolarization and the QRS complex), has
appeared feasible on the basis of available knowledge of
(1) cellular electrical changes associated with depolarization of cardiac cells:1"3 (2) the sequence of these changes
in the heart (pathway of depolarization);4-8 (3) geometry
and conductivity of the torso and its contents; and (4) the
physical theory describing current flow in three-dimenFrom the Department of Physiology and Biophysics, University of
Washington School of Medicine, Seattle, Washington.
Supported by U.S. Public Health Service Research Grant HL 0131522.
Received June 28, 1976; accepted for publication December 21, 1976.
sional, bounded, inhomogeneous conductors like the
torso.9-'7 If the forward problem were solved, it would
greatly strengthen the scientific basis of electrocardiography. Although all necessary information seems available,
past attempts to solve the forward problem during ventricular depolarization6' 18~23 appear to us either qualitative
and very difficult to evaluate or, when body surface maps
that can be compared with real body surface maps have
been produced, the studies do not show good agreement
between the two. An explanation for failure to solve the
forward problem may, we believe, be found in myocardial
cellular anatomy, the electrophysiology of cardiac cell-tocell conduction, and the manner in which cardiac cells
generate external currents. These are the subject of this
paper.
Cardiac cells are long and narrow (about 15 //.m in
diameter by 70 /im in length, with considerable variabil-
Tonic influence of the sympathetic nervous system on myocardial reactive hyperemia and on
coronary blood flow distribution in dogs.
P J Schwartz and H L Stone
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Circ Res. 1977;41:51-58
doi: 10.1161/01.RES.41.1.51
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1977 American Heart Association, Inc. All rights reserved.
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